tbuckley/cabot-search huggingface dataset:
Technology-enabled clinical trials: Intentional capture of source data (IDC) in the electronic-health record (EHR) and direct transfer to trial database (electronic data capture [EDC]) in a phase II multicenter trial.
Authors: Trevor Joseph Royce, Sam Falk, Forrest Xiao, Mariel Boyd, Lindsay Bramwell, Addison Shelley, Lauren Sutton, Ruth M. Morgan, Patricia Mader, Teresa Taiclet, Abigail Alve
Journal: Journal of Clinical Oncology (2023)

1568 Background: Traditional data collection for clinical trials can be cumbersome and inefficient. FDA guidance now promotes capturing clinical trial source data in electronic form and transmitting it to the EDC, recognizing that this should reduce double data entry and improve data quality and timeliness. Electronic data originators can include the EHR, which can be used during routine clinical care and for gathering data during a clinical investigation. We evaluated a pilot of structured EHR data transfer to EDC in a clinical trial setting. Methods: IDC capability in the EHR was developed and applied to a subset of patients for an open label prospective Phase II study. EHR variables, that include free text, standard dictionaries (eg CTCAEv5, CDISC, First Databank), and derived responses, were mapped to the electronic case report form (eCRF). Bulk transmission of IDC clinical data (adverse events, AEs; concomitant medications, CMs; past medical history, PMH) from the EHR to EDC was executed at a designated time point during study conduct. We assessed the quantity (records) and quality (queries) of data captured and transferred, and timeliness of entry. Data to be used for the production analysis of the trial was collected via eCRF in an EDC system in parallel per usual standards. Results: Data for 102 patients across 8 sites of care by 99 different users was captured in the EHR via IDC from 3/1/2021 to 9/9/2022 and transferred from EHR to EDC in bulk on 9/9/22. 3,958 data records were transferred (852 AEs; 1,581 CMs; 1,525 PMHs). Of the AEs, 99% had an associated grade. Of the CMs and PMHs, none were copy-forwarded (all were entered de novo). Regarding queries in the EDC for transcription error validation among matching records, EHR data produced 205 opened edit check queries from 12 edit checks across all domains (149 AEs, 0 CMs, and 56 PMHs). Regarding timeliness, 95% of matched records were entered in IDC prior to entry in the production EDC. Conclusions: For an open label Phase II study, clinical trial source data was captured electronically through IDC using the EHR as the data originator, and directly bulk-transmitted to EDC. This may enable the elimination of transcription of source data entry into eCRF and result in more timely access to the data in the EDC. Additional investigation into how IDC with EHR-to-EDC compares in quality to traditional EDC is warranted. Planned follow up research includes interviewing site users to evaluate their experiences with IDC data entry.
Correlation between Magee score and recurrence score in Indian patients with breast cancer.
Authors: Sissmol Davis, Dr Serene Sara John, Aditya Santoki, Sreedharan Sankaranarayanan, Pavithran Keechilat, Cherian Thampy, Yashaswini Shivashankara, Boben Thomas, Saphalta Baghmar, Rejiv Rajendranath, Narayanankutty Edavalath Warrier, Aju Mathew
Journal: Journal of Clinical Oncology (2023)

e12555 Background: Recurrence score (RS) from Oncotype Dx (ODx) test predict chemotherapy benefit in estrogen receptor (ER) positive, and HER2-negative patients with breast cancer. ODx is an expensive test in an Indian practice setting - cost of adjuvant chemotherapy is one-sixth of the cost of the test. Magee equations use histopathological variables, and semiquantitative results from ER, PR and Ki-67, to calculate Magee score (MS) and provide a cost-effective surrogate mechanism for predicting RS. We aimed to assess the correlation between MS and RS in an Indian setting. Methods: Pathology reports were obtained from oncologists in India. Immunohistochemistry for ER and PR were reported using the Allred system. Therefore, two methods were identified to estimate H-scores - using a calculated method (A), and using an expert-approximated (B) method. MS were calculated by a single investigator blinded to the RS. MS and RS were then assessed for correlation via the Pearson correlation method. MS were arbitrarily stratified into ≤ 15, 15 - 30, and ≥ 30, and their overall agreement (OA) or concordance with RS risk categories, ≤ 15, 15 - 30, and ≥ 30, were assessed. The OA was assessed by determining the proportion of patients in similar risk categories across low, intermediate and high-risk RS and MS. Results: Among 34 patients included in the study, 38% (13) had an RS ≤ 15, 38% (13) had an RS between 15 and 30, and 23% (8) had an RS ≥ 30. Correlation coefficient between MS and RS was 0.78 for both methods of estimation (p&lt;0.0001). The OA between MS-A and RS, and MS-B and RS were 59% (20/34) and 47% (16/34) respectively. The concordance between low-risk MS-A and RS is 78% (n=9) and between low-risk MS-B and RS is 50% (n=20). The concordance between high-risk MS-A and RS is 100% (n=2) and high-risk MS-B and RS is 100% (n=2). Conclusions: Although there is good correlation between RS and MS, the concordance between the two in similar risk categories is not optimal. Of the two methods to estimate H-score from Allred score, the calculated method seems to be more optimal. Our pilot study shows good correlation between MS and RS. We recommend that pathologists incorporate H-score as part of the reporting of ER and PR. A larger prospective study will be useful to test our hypothesis for the use of MS as a predictive tool for adjuvant chemotherapy in breast cancer.
Prognosis of squamous cell carcinoma of the breast by biological subtypes and the efficacy of radiotherapy: The Japanese Breast Cancer Registry analysis.
Authors: Mami Ogita, Makoto Kubo, Hiraku Kumamaru
Journal: Journal of Clinical Oncology (2023)

561 Background: Primary squamous cell carcinoma (SCC) of the breast is a rare disease, accounting for about 0.1% of all breast cancers. We aimed to determine the clinical features and prognosis of breast SCC, and the effect of radiotherapy by biological subtypes using the Japanese Breast Cancer Registry. Methods: We conducted a matched-pair analysis of 350,977 breast cancer patients with SCC or invasive ductal cancer (IDC) in the Japanese Breast Cancer Registry between 2004 and 2014. Inclusion criteria were female breast cancer patients who underwent surgery with stage I–III diseases, SCC or IDC, and age ≥ 18. Patients who received preoperative radiotherapy were excluded. We performed 1:1 SCC-IDC exact matching analysis by predominant subtypes in SCC: ER(-) and PgR(-)/HER2(-) or ER(+) and/or PgR(+)/HER2(-). Overall survival (OS), breast cancer-specific survival (BCSS), recurrence-free survival (RFS), and first locoregional or distant metastasis recurrence incidence were compared between IDC and SCC by Kaplan-Meier methods and log-rank test. In-field area recurrence was compared between those who received radiotherapy and those who did not. Results: We included 452 SCC and 182,707 IDC patients for the analysis. SCC patients were more likely to present with advanced stage disease compared to those with IDC. Among SCC patients, 59% was ER(-)/PgR(-)/HER2(-), 19% was ER(+)/PgR(+)/HER2(-), 8% was ER(-)/PgR(-)/HER2(+), 2% was ER(+)/PgR(+)/HER2(+), and 12% was data missing. Ten-year OS, BCS, and RFS rates were 70%, 80%, and 66% in SCC, and 88%, 93%, and 81% in IDC, respectively, and SCC carried a significantly worse prognosis than IDC (all P &lt; 0.001). For exact-matched analysis, 10-year BCS of ER(-)/PgR(-)/HER2(-) SCC patients was significantly worse than IDC (P = 0.02), whereas there were no significant differences between SCC and IDC of ER(+)/PgR(+)/HER2(-) patients in OS, BCS, and RFS. Among patients who received radiotherapy, no difference was found in in-field area recurrence between SCC and IDC in either ER(-)/PgR(-)/HER2(-) or ER(+)/PgR(+)/HER2(-) subtype. Conclusions: SCC of the breast was often diagnosed in an advanced stage and had a worse prognosis than IDC. More than half of them were triple-negative subtype. In the triple-negative subtype, SCC was an independent poor prognostic factor. No significant differences in in-field area recurrence after radiotherapy between SCC and IDC suggested that the effect of radiotherapy on local control for SCC was similar to IDC.
Trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low, hormone receptor-positive (HR+) unresectable and/or metastatic breast cancer (mBC): Exploratory biomarker analysis of DESTINY-Breast04.
Authors: Shanu Modi, Naoki Niikura, Toshinari Yamashita, William Jacot, Joohyuk Sohn, Eriko Tokunaga, Maria Jesus Vidal, Yeon Hee Park, Keun Seok Lee, Yeesoo Chae, Naoto T. Ueno, Aleix Prat, Fumitaka Suto, Yusuke Kuwahara, Robert McEwen, Wenqin Feng, Hiroki Goto, Cecilia Orbegoso, David A. Cameron, Junji Tsurutani
Journal: Journal of Clinical Oncology (2023)

1020 Background: DESTINY-Breast04 (NCT03734029) showed improved progression-free survival (PFS) and overall survival for T-DXd vs TPC in pts with HER2-low (IHC 1+ or 2+/ISH-negative) mBC. We present exploratory biomarker analysis in pts with HER2-low, HR+ mBC. Methods: Biopsy specimens collected from 326 pts after prior treatment were analyzed using RNA-sequencing and intrinsic subtypes estimated by PAM50 gene expression. ESR1 and PIK3CA mutations and known gene alterations associated with resistance to CDK4/6 inhibitors (CDK4/6i) were assessed in baseline (BL) circulating tumor DNA (ctDNA) samples from 414 pts by Guardant OMNI. Association with objective response rate (ORR) and PFS was evaluated. Results: Frequencies of BL intrinsic subtypes in the T-DXd and TPC arms were 41.3% and 46.6% for Luminal A, 48.0% and 37.9% for Luminal B, and 9.0% and 11.7% for HER2 enriched, respectively. According to ctDNA results in the T-DXd and TPC arms, respectively, ESR1 mutations were observed in 51.3% and 54.0% of pts, PIK3CA mutations in 36.1% and 41.6% of pts, and at least one CDK4/6i resistance marker (pts with prior CDK4/6i) was detected in 71.5% and 70.2% of pts. Improved T-DXd efficacy was seen regardless of intrinsic subtype (Luminal A, Luminal B, HER2-enriched), ESR1 mutation, PIK3CA mutation, or CDK4/6i resistance markers (Table). Conclusions: Greater clinical benefit was consistently observed with T-DXd vs TPC independent of intrinsic subtype, ESR1 mutation, PIK3CA mutation, or known CDK4/6i resistance marker status. Clinical trial information: NCT03734029 . [Table: see text]
Potential therapeutic implications of next generation sequencing (NGS)-based molecular profiling in HR+/HER2- metastatic breast cancer (mBC).
Authors: Barbara Avesani, Elena Giontella, Alberto Caldart, Alessandro De Noni, Alice Muzzarelli, Giulia Borghesani, Jessica Insolda, Pamela Biondani, Veronica Parolin, Francesca Pellini, Aldo Scarpa, Alessia Nottegar, Rita T Lawlor, Andrea Mafficini, Ida Paris, Angelo Minucci, Tina Pasciuto, Alessandra Fabi, Elena Fiorio, Michele Milella
Journal: Journal of Clinical Oncology (2023)

e13079 Background: BC is the most frequent malignancy in women and is potentially sensitive to hormonal treatment (HR+, HER2+ or -) in approximately 70% of cases. PIK3CA is among the most frequently mutated genes in BC (approximately 40% of cases) and its mutations portend sensitivity to PI3K inhibitors, such as alpelisib, in combination with hormonal treatment in HR+/HER2- cases. However, extended NGS-based testing is not currently recommended by national and international guidelines. Methods: Women aged 18 years or older, with cytological or histological diagnosis of HR+/HER2- mBC, for whom suitable tissue samples were available, were subjected to extended NGS profiling using the FoundationOne, analyzing 324 genes and gene signatures, such as tumor mutational burden (TMB) and microsatellite instability (MSI); and Illumina TruSight Oncology 500, analyzing 500 genes. DNA was isolated from formalin-fixed, paraffin-embedded (FFPE) samples, from either the primary or metastatic site. Results: Patients (pts) were analyzed (ductal histology: 52%; lobular: 15%; mixed ductal-lobular: 12%; NOS: 21%), among which 7 (12%) had inadequate pathological material and were considered screening failures. A full molecular report was obtained in 53 patients. The most frequent pathogenic and likely pathogenic alterations (class 5 and 4), listed in descending order of prevalence, are: PIK3CA in 51% of pts (E545K&gt;H1047R&gt;N345K&gt;E542K); CDH1 in 21% (prevalence in lobular carcinoma: 75%; in ductal carcinoma: 3,5%). CCND1 in 28% (all amplifications). FGFR1-2 in 21%, TP53 in 15%, WHSC1L1 and ZNF703 in 13%, RAD21 and TBX3 in 9%. Homologous recombination-related genes, such as BRCA1/2 and PALB2 were altered in &lt;5% while ATM altered in 9% of cases. Many other pathogenic mutations (affecting 69 individual genes) were identified, all with a prevalence &lt;10%. TMB was high (&gt;17 mutations/Mb) in 13% of cases, in one of which MSI was also detected. Conclusions: In our analysis PIK3CA was confirmed to be the most frequently mutated gene (51% of cases); however, due to the specific European regulatory constraints, it was deemed to be actionable in a minority of cases, suggesting that NGS profiling should be performed early on after the diagnosis of metastatic disease, in order to inform the overall therapeutic strategy. Other potentially actionable alterations (FGFR1/2, AKT, HER2 ex 20 mutations) emerged from extended NGS profiling, suggesting its potential utility in selected HR+/HER2- mBC pts.
Somatic mutations in tumor-adjacent normal breast tissue in young women with high risk family history.
Authors: Mariya Rozenblit, Aleksandra Suwalska, Erin Wysong Hofstatter, Emily Reisenbichler, Malini Harigopal, Michal Marczyk, Lajos Pusztai
Journal: Journal of Clinical Oncology (2023)

576 Background: It’s incompletely understood why some women without germline breast cancer predisposing mutations develop early onset breast cancer. Breast cancer in young women is often more aggressive, with high histologic grade, worse prognosis, and higher risk of recurrence. We hypothesize that these women have somatic mutations in the normal breast tissue that contribute to breast cancer tumorigenesis. Methods: Whole exome sequencing (WES) data was analyzed from normal tissue adjacent to breast tumor and compared to matched peripheral blood (n=28). All patients were &lt;50yo, had high risk family history as per NCCN guidelines, and had negative Ambry Genetics panel testing. FFPE sections were reviewed by two pathologists to identify normal breast tissue furthest away from tumor. WES was performed on Illumina HS4000 using 100-base pair paired-end reads. Samples were mapped to the human reference genome (vGRCh38). PCR duplicates were marked (Picard), and indel regions were adjusted (GATK). High-quality germline variants (HaplotypeCaller), somatic mutations (Mutect), and indels (IndelGenotyper) were called. Low-quality variants were filtered out. The classification and number of mutations per gene per sample were extracted and analyzed. Results: Majority of patients were white (86%), median age 45, with invasive ductal carcinoma (86%), ER+/PR+/HER2- (100%). Median somatic variants per sample were 97 (range: 45-285), all single nucleotide variants, mostly missense mutations, C&gt;T conversions were seen in 45% of mutations. This suggests cytidine deaminase (APOBEC) involvement. All samples had alterations in at least one of the top ten affected genes which include transcription factors in zinc finger family (listed below). Zinc finger proteins play a key role in tumorigenesis, cancer progression and metastasis in a variety of cancers. Upregulation of zinc finger proteins has been associated with worse prognosis in breast cancer. Conclusions: We describe novel somatic mutations in zinc finger proteins in normal breast tissue adjacent to tumor that may contribute to early onset breast cancer in patients with high risk family history. [Table: see text]
The inclusion of health-related quality of life and other patient-reported outcomes in landmark trials for Food and Drug Administration oncology drug approvals: An analysis of cancer drug approvals between 2006 and 2022.
Authors: Ademola Samuel Ojo, Ahmed Ali
Journal: Journal of Clinical Oncology (2023)

1569 Background: How patients feel and function are essential elements of the clinical benefit of interventions which is often not captured by traditional measures of clinical benefit such as progression-free survival and overall survival. Health-related quality of life, functional status, symptom burden, and other patient-reported outcomes (PROs) assess the impact of interventions from the patient’s point of view. The aim of this study is to assess the inclusion of PROs in landmark trials leading to FDA oncology drug approvals. Methods: This is a retrospective cross-sectional study of pivotal trials leading to FDA oncology approvals between January 2006 and December 2022 based on the FDA oncology approval notifications. The trial protocols of all pivotal trials were evaluated for inclusion of health-related quality of life or other PROs as an outcome measure. The approved therapies were classified into first-line, adjuvant/maintenance, and second or later line of treatment. Chi-square tests were used to assess the relationship between the line of treatment and the inclusion of PROs in the trial protocol. Results: There were 420 oncology approvals during the study period with the highest number of approvals in a single year in 2020 (56) and the least in 2007 (7). Lung cancer has the highest number of approvals (61, 14.5%) followed by lymphoma (50, 12%), leukemia (49, 11.7%), genitourinary malignancies (48, 11.4%), breast cancer (36, 8.6%), gastrointestinal malignancies (32, 7.6%), plasma cell disorders (30, 7.1%) melanoma (20, 4.8%), gynecological malignancies (20, 4.8%), hepatobiliary malignancies (14, 3.3%) and head/neck cancers (14, 3.3%). The approved therapies were first line (146, 34.8%), second or higher line (226, 53.8%), and adjuvant/maintenance therapies (48, 11.4%). PROs were included in 40.7% of the pivotal trials. There is a rising trend in the inclusion of PROs from 5.5% of pivotal trials in 2006 to 31% in 2022. Trials on first-line therapies are more likely to include PROs compared to second or higher-line therapies (44.5% vs 36.7%; p = 0.13). Conclusions: Although there is a rising trend in the inclusion of health-related quality of life and other PROs in pivotal trials for FDA oncology drug approvals, most pivotal trials did not include PROs as outcome measures.[Table: see text]
Indirect treatment comparison of first-line CDK4/6-inhibitors in post-menopausal patients with HR+/HER2- metastatic breast cancer.
Authors: Joseph J Zhao, Khi Yung Fong, Yiong Huak Chan, Jeremy Chee Seong Tey, Shaheenah S. Dawood, Soo-Chin Lee, Richard S. Finn, Raghav Sundar, Joline SJ Lim
Journal: Journal of Clinical Oncology (2023)

1071 Background: In phase III studies, the CDK4/6-inhibitors palbociclib, ribociclib, and abemaciclib all have demonstrated similar clinical efficacy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC) with regards to the primary endpoint of progression-free survival (PFS). However, the lack of overall survival (OS) benefit in the PALOMA-2 study is inconsistent with the OS benefit seen with the other two CDK4/6-inhibitors. This study sought to elucidate indirect treatment survival outcomes between CDK4/6-inhibitors in this setting. Methods: Phase III randomized controlled trials comparing first-line aromatase inhibitor with or without a CDK4/6-inhibitor in post-menopausal patients with HR+/HER2- MBC. A graphical reconstructive algorithm was utilized to retrieve patient level time-to-event data from reported Kaplan-Meier OS and PFS curves. Survival analyses were conducted with Cox proportional hazards model with a shared-frailty term incorporated to account for inter-study differences. Two-stage indirect treatment comparison model was conducted as a sensitivity analysis. Results: Three randomized phase III trials – PALOMA-2, MONALEESA-2 and MONARCH-3 – comprising 1,827 patients were included. Indirect pairwise comparison of all CDK4/6-inhibitor showed no significant PFS differences across one-stage and two-stage models (all p&gt;0.05). Likewise, indirect treatment comparison between ribociclib vs palbociclib (one-stage: HR=0.903, 95%-CI: 0.746-1.094, p=0.297), abemaciclib vs palbociclib (one-stage: HR=0.843, 95%-CI: 0.690-1.030, p=0.094) and abemaciclib vs ribociclib (one-stage: HR=0.933, 95%-CI: 0.753-1.157, p=0.528) failed to demonstrate a significant OS difference. Conclusions: Findings from this indirect treatment comparison suggest no significant PFS or OS differences between CDK4/6-inhibitor agents when combined with an aromatase inhibitor in post-menopausal patients with HR+/HER- MBC. [Table: see text]
Interim analyses (IA) of the giredestrant (G), G + abemaciclib (A), and G + ribociclib (R) arms in MORPHEUS Breast Cancer (BC): A phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced/metastatic BC (ER+, HER2– LA/mBC).
Authors: Mafalda Oliveira, Amir Sonnenblick, Hope S. Rugo, Kyung Hae Jung, Einav Gal Yam, Sara A. Hurvitz, Cristina Hernando, Seock-Ah Im, Vanessa Breton, Ann Collier, Richard B. Schwab, Jing Zhu, Joohyuk Sohn
Journal: Journal of Clinical Oncology (2023)

1061 Background: Limitations of current approved endocrine therapies (ETs), a mainstay tx for ER+ BC, include incomplete ER signaling inhibition. Novel ETs, such as selective estrogen receptor antagonists and degraders (SERDs), may help overcome this. G, a potent, nonsteroidal, oral (PO) SERD, is well tolerated and has shown robust ER occupancy and encouraging antitumor activity as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (P). MORPHEUS BC (NCT04802759) is evaluating the safety and efficacy of G tx combinations in ER+, HER2– LA/mBC. We present results from the 16-week IA of G and G + CDK4/6i (A or R). Methods: Eligible pts had disease progression on 1–2 lines of ET (including a CDK4/6i) for LA/mBC. Pts were randomized 1:6 (planned n = 15 per arm) to receive G (30 mg PO QD; control arm), G + A (150 mg PO BID), or sequentially, G + R (600 mg PO QD) until disease progression/unacceptable toxicity. The study was not designed to make explicit power and type I error considerations for a hypothesis test. Primary endpoints were safety and objective response rate; other endpoints included progression-free survival, overall survival, clinical benefit rate, disease control rate (DCR), duration of response, and pharmacokinetics. Genetic alterations were defined using baseline circulating tumor DNA. Results: As of Feb 4, 2022, 15 pts were enrolled in the G + A arm; 73% received one prior line of tx in the LA/mBC setting; 27% received prior fulvestrant; 73% had liver metastases at baseline (BL). As of Sept 22, 2022, 11 and 16 (of whom 14 were evaluable) pts were enrolled in the G and G + R arms, respectively; 64%/86% received one prior line of tx in the LA/mBC setting; 73%/36% received prior fulvestrant; 73%/57% had liver metastases at BL. Three pts had a partial response (PR; G + A, n = 1; G + R, n = 2); 19 had stable disease (G, n = 5; G + A, n = 7; G + R, n = 7). DCRs were 36% (G), 40% (G + A), and 50% (G + R). Safety is shown. Conclusions: G combined with a CDK4/6i (A or R) was well tolerated, with no unexpected safety signals. Three PRs were seen in this heavily pretreated population of pts with disease progression post-CDK4/6i tx. This study provides the first data supporting the combinability of G with the CDK4/6is A and R, in addition to P as seen in prior studies. G can therefore be combined with all three approved CDK4/6is. Clinical trial information: NCT04802759 . [Table: see text]